Tumour characteristics of bilateral screen-detected cancers and bilateral interval cancers in women participating at biennial screening mammography

Accepted Manuscript Title: Tumour characteristics of bilateral screen-detected cancers and bilateral interval cancers in women participating at biennial screening mammography Authors: Rob van Bommel, Joost RC Lameijer, Adri C Voogd, Joost Nederend, Marieke WJ Louwman, Wikke Setz-Pels, Luc J Strobbe, Vivianne CG Tjan-Heijnen, Lucien EM Duijm PII: DOI: Reference:

S0720-048X(18)30339-5 https://doi.org/10.1016/j.ejrad.2018.09.026 EURR 8319

To appear in:

European Journal of Radiology

Received date: Revised date: Accepted date:

22-3-2018 20-9-2018 21-9-2018

Please cite this article as: van Bommel R, Lameijer JR, Voogd AC, Nederend J, Louwman MW, Setz-Pels W, Strobbe LJ, Tjan-Heijnen VC, Duijm LE, Tumour characteristics of bilateral screen-detected cancers and bilateral interval cancers in women participating at biennial screening mammography, European Journal of Radiology (2018), https://doi.org/10.1016/j.ejrad.2018.09.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tumour characteristics of bilateral screen-detected cancers and bilateral interval cancers in women participating at biennial screening mammography

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Rob van Bommel1, Joost RC Lameijer1, Adri C Voogd2,3,4, Joost Nederend1, Marieke WJ Louwman3, Wikke Setz-Pels1, Luc J Strobbe5, Vivianne CG Tjan-Heijnen4, Lucien EM

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Duijm6,7

Department of Radiology1, Catharina Hospital, Michelangelolaan 2, 5623EJ, Eindhoven, The

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Netherlands

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Department of Epidemiology2, Maastricht University, GROW, P Debyelaan 1, 6229 HA,

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Maastricht, The Netherlands

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Department of Research3, Netherlands Comprehensive Cancer Organization (IKNL),

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Godebaldkwartier 419, 3511 DT, Utrecht, The Netherlands Department of Internal Medicine4, Division of Medical Oncology, GROW, Maastricht

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University Medical Centre, PO Box 5800, 6202 AZ, Maastricht, The Netherlands Department of Surgery5, Canisius Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ,

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Nijmegen, The Netherlands

Department of Radiology6, Canisius Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, The Netherlands

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Dutch Expert Centre for Screening7, Wijchenseweg 101, 6538 SW, Nijmegen, The Netherlands

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Abstract Background Unilateral interval breast cancers show less favourable prognostic features than unilateral screen-detected cancers, but data on tumour characteristics of bilateral interval cancers in a systematically screened population are sparse. Therefore, we compared tumour characteristics of bilateral interval cancers with those of bilateral screen-detected cancers.

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Methods

We included all 468,720 screening mammograms of women who underwent biennial

screening mammography in the South of the Netherlands between January 2005 and January

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2015. We collected breast imaging reports, biopsy results and surgical reports of all recalled women and of all women who presented with interval breast cancer. In women with

synchronous bilateral breast cancer, the tumour with the highest tumour stage was defined as

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the index cancer. For comparison of data between both groups Fisher exact test and Chi-

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square test were used.

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Results

Synchronous bilateral cancer was diagnosed in 2.2% of screen-detected cancers (64/2,947)

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and in 3.2% of interval cancers (24/753) (P=0.1). Index tumours of bilateral screen-detected cancers and interval cancers showed similar characteristics, except for a larger proportion of

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T-stage 2 or worse (T2+) cancers among interval cancers (16/24 (66.7%) versus 23/58 (39.7%) (P=0.03). Index cancers, compared to contralateral cancers, were less frequently

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stage T1 in both bilateral screen-detected cancers and bilateral interval cancers (35/64 (60.3%) versus 40/64 (88.9%) (P=0.001) and 8/24 (33.3%) versus 18/24 (85.7%) (P<0.001), respectively). In bilateral screen-detected cancers, contralateral cancers were more often stage

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1a-c (P<0.001) compared to index cancers. In bilateral index cancers, index cancers were more often of the lobular subtype (P<0.001). Conclusion

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Index cancers of bilateral screen-detected cancers and bilateral interval cancers show significant differences in tumour size, whereas nodal status, receptor status and final surgical treatment are comparable. In bilateral screen-detected cancer, index cancers had a significantly higher tumour stage. In bilateral screen-detected cancer, index cancers were more often the ductal invasive subtype compared to contralateral cancers.

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Keywords: Bilateral breast cancer; Screening mammography; Index cancer; Contralateral cancer; Synchronous breast cancer.

Introduction Breast cancer is one of the most common malignancies diagnosed in women nowadays. Many western countries have implemented regional or nationwide breast cancer screening programmes to detect breast cancer at a less advanced stage. Screening mammography, in

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combination with more effective treatments, results in decreased mortality of breast cancer [14]

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Despite the screening programmes, 20-25% of breast cancers in a systematically screened population are detected during the interval between two screening rounds, the so-called interval cancers [5,6]. One of the challenges of breast cancer screening is to reduce the

proportion of interval cancers, as they have proven to be relatively large, poorly differentiated

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tumours, with a worse disease-free and overall survival compared to screen-detected cancers

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[7].

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A subgroup of patients with breast cancer has synchronous bilateral cancer, with the

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contralateral cancer diagnosed within 3 months of the initially diagnosed breast malignancy [8-9]. In symptomatic patients, 0.7-2.3% of breast cancers are bilateral [9-11] and 2.2% of

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screen-detected cancers are bilateral in a systematically screened population [8]. Several studies in predominantly symptomatic patients, found that bilateral cancers show more favourable tumour characteristics than unilateral cancers, with a higher proportion of invasive

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lobular cancer [8], lower T-stage [12] and a higher proportion of hormone receptor expression [10]. This is mainly due to the smaller secondary detected tumour [8,10,12]. Despite these

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findings, many authors report a worse overall survival for bilateral breast cancer compared to unilateral breast cancer. [13-16]. Several studies have reported on tumour features of unilateral screen-detected cancers and

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interval cancers.[7,17] However, data on bilateral breast cancer at screening mammography are sparse and data on bilateral interval cancer are, to our knowledge, almost lacking (Figure 1). In a previous study we focused on bilateral interval cancers and described how they differ from unilateral interval cancers [18]. The quality and effect of screening mammography programmes are determined not only by the characteristics of screen-detected cancers (unilateral or bilateral) but also by those of unilateral and bilateral interval cancers. In the current study, we therefore investigated to what extent tumour characteristics of bilateral 3

interval cancers differ from those of bilateral screen-detected cancers and we further explored differences between index tumours and contralateral tumours in bilateral screen-detected cancers and bilateral interval cancers.

Methods Study population

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We included all screening examinations obtained in a breast cancer screening region in the south of the Netherlands, between January 1, 2005 and January 1, 2015. A total of 468,720

screening mammograms were obtained, both initial and subsequent screens. Both screen-film

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mammography (SFM) and full-field digital mammography (FFDM) were included in the study, since the transition from SFM to FFDM was made in 2009/2010. All women

participating in the screening programme were asked to give written informed consent to use their screening data and follow-up data for scientific purposes. In total, four women refused

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usage of their data and were excluded from analysis. Ethical approval by our local

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Institutional Review Board was not required for this study, according to the Dutch Central

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Committee on Research involving Human Subjects (CCMO) in The Hague.

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Screening procedure

Details of the Dutch nationwide breast cancer screening programme, offering biennial

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screening mammography for women aged 50-75 years, have been published elsewhere [19,20]. In summary, all screening mammograms were obtained by a team of specialized mammography radiographers in one of four screening units (one fixed and three mobile

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units), and all screening mammograms were double-read by two certified screening radiologists, with more than 20 years of experience with screening mammography and clinical

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breast imaging. During the study period, the screening group consisted of 15 radiologists and each radiologist evaluated at least 3,000 mammograms yearly and all radiologists participated in clinical breast imaging. At the start of 2005, the mean length of experience of the 8 interpreting radiologists with screening mammography was 103 months (range, 63-119

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months). Four more radiologists started interpreting screening mammograms between 20052010 and another 3 radiologists started interpreting screening mammograms between 20112013 Prior screening mammograms were always available for comparison at the time of subsequent screening. To facilitate this comparison, most recent screen-film mammograms were digitized

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using a film scanner and archiver designed for mammography (DigitalNow; R2/Hologic, Bedford, MA). Diagnostic work-up All recalled women received physical examination by the surgeon or the dedicated breast nurse at the breast unit of a hospital, and additional breast imaging was performed in the radiology department. Dependent on the findings at physical examination and mammography

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and dependent on local diagnostic work-up protocols, further diagnostic evaluation could include additional mammographic views, breast tomosynthesis, contrast-enhanced spectral mammography (CESM), (3D) breast ultrasound, magnetic resonance imaging (MRI),

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percutaneous fine needle aspiration cytology (FNAC), core needle biopsy (CNB), stereotactic biopsy, magnetic resonance guided biopsy or open surgical biopsy. All radiological findings were classified according to the fourth edition of the Breast Imaging Reporting and Data

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System lexicon, (BI-RADS) [21,22]. Lesions classified as BI-RADS IV or V were routinely biopsied and BI-RADS III lesions were either biopsied or followed up, as discussed in the

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multidisciplinary breast team. Patients with radiological findings classified as BI-RADS I or

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II were again referred to the breast cancer screening programme.

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Follow-up procedure

For the detection of interval cancers and bilateral breast cancers, all women in our breast

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screening programme were followed during a period of about 2 years (until the next biennial screening mammography examination). Details on the methods of detecting interval cancers have been published previously [23-25]. Most interval cancers were identified by linkage of

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the screening records to the Netherlands Cancer Registry (NCR), Netherlands Comprehensive Cancer Organization (IKNL) and regional pathology laboratories and radiotherapy centres. In

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all women recalled or diagnosed with interval cancer, we collected all available clinical and radiological data, including: screening mammography findings, clinical data, clinical breast imaging reports, biopsy results, and breast surgery reports.

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In patients with interval cancer, all screening mammograms prior to the detection and the diagnostic mammogram which was obtained at the time of detection, were reviewed by three experienced screening radiologists. Breast density was categorized according to the BI-RADS lexicon [21,22] . In bilateral breast cancers, the cancer with the more advanced stage (or, in cases where both tumours had the same stage, the largest tumour at pathology), was defined as the index tumour [9]. We only included synchronous bilateral breast cancers, defined as histological confirmation of the contralateral tumour within three months after histological 5

confirmation of the prior breast cancer. Clinical T-stage was defined prior to neoadjuvant therapy (either chemotherapy or endocrine therapy). In cases undergoing neoadjuvant therapy, local staging was usually investigated using MRI. Lobular carcinoma in situ was not considered to be a breast malignancy. Statistical analysis All data were entered into a computerized spreadsheet (Excel; Microsoft, Redmond, WA,

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USA), and statistics were performed using Statistical Package for Social Science 22.0 (SPSS Inc. Chicago, IL). The Chi-square or Fisher exact test was used to test differences in tumour characteristics between bilateral interval cancers and bilateral screen-detected cancers and

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between index and contralateral tumours of both bilateral interval cancers and bilateral screen-detected cancers.

Results

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Overall screening results

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The overall screening results have already been published elsewhere [van Bommel, et al.

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2018]. In summary, during a 10 year period between January 1, 2005 and January 1, 2015,

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468,720 screening mammograms were obtained ( 160,776 SFM screens and 307,944 FFDM screens). The recall rate was 26.5 per 1,000 screened women (12,398/468,720), with an

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overall cancer detection rate of 6.3 per 1,000 screened women (2,947/468,720, PPV 23.8%). 753 women were diagnosed with interval cancer, representing 20.4% of all women diagnosed

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with breast cancer in the screened population, resulting in a programme sensitivity of 79.6%. Bilateral cancer rate at screening mammography A total of sixty-four out of 2,947 screen-detected cancers were bilateral and bilateral breast

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cancer was diagnosed in 24 out of 729 women with interval breast cancer (2.2% versus 3.2%), (P=0.08)

Comparison of the index cancers of bilateral screen-detected cancers and bilateral

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interval cancers

The distribution of breast density at the latest screening mammogram was comparable for bilateral screen-detected cancers and interval cancers (P=0.53, Table 1). There were six ductal carcinoma in-situ cases (DCIS) in the screen-detected group (9.4%, 6/64) and none among women with interval cancer. Index cancers of invasive, bilateral interval cancers were larger than those of bilateral screen-detected cancers, with a larger proportion of T2-4 cancers 6

among interval index cancers (66.7% (16/24) versus 39.7% (23/58), (P=0.03). There was no difference in nodal involvement between both groups, 39.7% (23/58) for screen-detected cancers versus 54.2% (13/24) for interval cancers (P=0.23). We also found no significant differences in tumour histology distribution (e.g., invasive ductal or invasive lobular carcinoma), histological grade, oestrogen / progesterone / HER2 receptor expressions or final surgical treatment.

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Characteristics of index cancers versus contralateral cancers in women with bilateral screen-detected cancer

Contralateral cancers comprised a higher percentage of ductal carcinoma in situ (DCIS) than

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index cancers (25.0% (16/64) versus 9.4% (6/64), (P=0.006, Table 2) in recalled women

diagnosed with bilateral breast cancer. The majority of cancers in both groups were of the ductal type. There was a higher proportion of contralateral invasive lobular subtype cancer in

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women with an invasive index tumour of the lobular type than in women with an invasive ductal index tumour ( 41.7% (5/12) versus 7.7% (3/39), (P=0.01). Index cancers had a less

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favourable tumour size, with 39.7% (23/58) of invasive cancers showing T2-4 (>20 mm)

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versus 11.1% ( 5/45) of the contralateral breast cancers (P=0.001). Differences in nodal

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involvement between index cancers and contralateral cancers were not statistically significant (39.7% (23/58) versus 24.4% (11/45), P=0.14). With respect to histological grading of invasive screen-detected cancers, contralateral cancers were more frequently grade I (60.0%

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(27/45) versus 32.8% (19/58), (P=0.006)). Receptor status and type of final surgical treatment were comparable for both groups.

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Comparison of contralateral cancers in women with bilateral screen-detected cancers and bilateral interval cancers

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Contralateral cancers in women, either diagnosed with bilateral breast cancer after recall or diagnosed with bilateral interval cancer, showed comparable tumour characteristics, except of a higher percentage of invasive ductal cancers (85.7% (18/21) versus 73.3% (33/45)) and no

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invasive lobular cancers (0% versus 22.2% (10/45)) among contralateral interval cancers (P=0.048, Table 1). Characteristics of index cancers versus contralateral cancers in women diagnosed with bilateral interval cancer The comparison between index cancers and contralateral cancers in bilateral interval cancer has already been published elsewhere [van Bommel et al. 2018]. In summary, compared to 7

contralateral cancers, invasive index cancers were more frequently of the lobular subtype (37.5% (9/24) versus 0% (0/21), (P=0.001), Table 2) and showed a less favourable tumour size (T1a-c, 33.3% (8/24) versus 85.7% (18/21), (P<0.001)). We observed no significant differences in receptor status and final surgical treatment between index cancers and contralateral cancers.

Discussion

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To our knowledge, this is the first study comparing tumour characteristics of bilateral interval breast cancer with bilateral screen-detected breast cancer, in a biennial screened population.

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We found a comparable incidence of bilateral screen-detected cancer (2.2%) and bilateral interval cancer (3.2%) in our biennial screening mammography programme.

Index tumours of bilateral interval cancers were larger than those of bilateral screen-detected cancers. No differences in nodal stage, histological grade, receptor status or final surgical

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treatment were observed.

In our previous study we showed that index cancers of bilateral interval cancers were more

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often of the invasive lobular subtype, had a less favourable tumour size (T-stage) and we

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suggested a trend towards higher hormone receptor expression in contralateral cancers [18]. In this study we showed that in bilateral screen-detected cancers, contralateral cancers were

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more frequently DCIS, and invasive contralateral cancers were smaller and better differentiated than index cancers.

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Bilateral cancers are infrequently encountered in screening mammography programmes and their incidences are in the same range of the bilateral cancer incidence in a symptomatic

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population (0.7-3.2%) [26-27].

Compared to the index tumours of bilateral screen-detected cancers, index tumours of bilateral interval cancers more frequently showed a locally advanced tumour stage (tumour stage T2 and higher). Unilateral interval cancers are known to be larger and usually have a

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more advanced nodal stage and less favourable tumour characteristics than screen-detected tumours [28-31] and our findings have shown that this statement is also applicable to bilateral interval cancers. In bilateral screen-detected cancers, about 10% of the index cancers and 25% of contralateral cancers were DCIS. In bilateral interval breast cancers, we observed only 3 cases of ductal carcinoma in-situ (none of them as index cancer) among the total of 48 interval cancers This 8

shows that in systematically screening, not all findings have the same clinical significance. The sensitivity of screening mammography is better for the detection of unilateral, invasive ductal cancers than for invasive lobular cancers, probably resulting in a larger proportion of invasive interval cancers of the lobular subtype [6,15,30,32]. We also observed a relatively large proportion of 37.5% of invasive lobular cancers among the index cancers of bilateral interval cancers. In our series, index cancers of bilateral interval cancers tended to be more frequently of the invasive lobular type than did the index cancers of bilateral screen-detected

due to the relatively small sample size of bilateral cancers in our study.

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cancers, but this difference did not reach statistical significance. These findings are probably

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We found a higher proportion of contralateral invasive lobular cancer in women with an invasive index tumour of the lobular type than in women with an invasive ductal index

tumour. Invasive lobular cancer is known to be a diagnostic challenge at mammography and

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ultrasonography [33], whereas MRI has a high sensitivity for the detection of even small foci of invasive lobular cancer [34]. Therefore, when dealing with an invasive lobular cancer

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(either screen-detected or presenting as interval breast cancer), pre-operative MRI should be

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considered in order to determine the extent of the tumour and to assess the contralateral breast

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[35].

Our study has certain strengths and limitations. The large cohort of 468,720 screening

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mammograms and extensive follow-up enabled us to investigate bilateral breast cancers at screening mammography. The data provided us insight into many parameters, including mammographic features, tumour characteristics and surgical treatment. The follow-up period

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of two years, however, rendered it impossible to report on long term morbidity or mortality. The literature shows that, despite more favourable tumour characteristics (i.e., a higher

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proportion of invasive lobular cancers, smaller tumours and a higher proportion of positive receptor status), women with bilateral breast cancer have a worse prognosis than those with unilateral breast cancer [13-16,36]. Obviously, both tumours have a risk of distant spread and

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thereby may compromise long term outcomes. Of note, we did not analyse the use of systemic therapy and whether the detection of bilateral cancer has changed the decision-making process in the use of systemic therapy. The quality and effectiveness of screening mammography programmes is determined by the stage distribution and tumour characteristics of unilateral and bilateral screen-detected cancers and interval cancers. Although we found a low prevalence of bilateral breast malignancies in our screened population, their early detection may influence the therapeutical approach 9

(breast conserving surgery versus mastectomy) and prognosis. Therefore, screening radiologists and clinical breast radiologists should vigorously examine both breasts to rule out or to confirm simultaneous bilateral disease. Our study comprises a screening period of 10 years (2005-2014). In this period, much has changed in breast cancer screening and in clinical practice. For example, full-field digital screening mammography replaced screen-film mammography in 2009-2010, and breast

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tomosynthesis and MR mammography are increasingly used at clinical work-up. Therefore, more and smaller contralateral tumours might be found in the more recently screened patients than at an earlier time. Finally, although very limited data are available on bilateral screen-

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detected cancers and even less on bilateral interval cancers, we realize that we are reporting

on a small subset of bilateral cancers. Due to the relatively small series of 64 bilateral screendetected cancers and 24 bilateral interval cancers, differences between both groups may not

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have reached statistical significance and due to small numbers a multivariate analysis was not

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feasible.

In summary, bilateral screen-detected cancers and bilateral interval cancers are infrequently

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diagnosed. Index cancers and contralateral cancers of bilateral screen-detected cancers and

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tumour histology and tumour size.

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Funding None.

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bilateral interval cancers show statistically significant differences in DCIS proportions,

Availability of data and materials

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

Competing interests

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All of the authors declare that they have no conflict of interest.

Consent for publication As stated above, all women participating in our screening programme and included in our analysis gave written permission to use their data for scientific purposes.

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Ethics approval and consent to participate Women participating in our screening programme are asked to give written permission for the use of their data for quality assurance and scientific purposes. Four women screened at our units did not give this permission and they were excluded from analysis. The Central Committee on Research Involving Human Subjects (CCMO) in The Hague, The Netherlands,

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waived ethical approval for this study.

Acknowledgments

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The authors would like to thank screening organization Bevolkings Onderzoek Zuid (BOZ) for data management.

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[35] Debald M, Abramian A, Nemes L, Dobler M, Kaiser C, Keyver-Paik MD, et al., Who may benefit from preoperative breast MRI? A single-center analysis of 1102 consecutive patients with primary breast cancer. Breast Cancer Res Treat 153 (2015); 531-7 DOI: 10.1007/s10549-015-3556-3 [36] Karakas Y, Kertmen N, Lacin S, Aslan A, Demir M, Ates O, Aksoy S, Altundag K,

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unilateral breast cancers. J BUON 22 (2017):623-7

[37] Maes RM, Dronkers DJ, Hendriks JH, Thijssen MA, Nab HW (1997) Do nonspecific minimal signs in a biennial mammographic breast cancer screening programme

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need further diagnostic assessment? Br J Radiol 70:34-8 DOI:

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[40] Weber RJ, van Bommel RM, Louwman MW, Nederend J, Voogd AC, Jansen FH, Tjan-Heijnen VC, Duijm LE (2016) Characteristics and prognosis of interval cancers after biennial screen-film or full-field digital screening mammography. Breast Cancer Res Treat 158: 471-83 DOI: 10.1007/s10549-016-3882-0

17

M

A

N

U

SC R

IP T

Figr-1

A

CC E

PT

ED

Fig 1. Almost 2 years after a negative first screen mammography, a woman was referred by her physician to a regional hospital for the evaluation of a palpable mass in the upper outer quadrant of the right breast. mammography (A) showed no suspicious findings. Ultrasound (B) showed a solid mass (calipers) biopsy revealed invasive lobular carcinoma. As the primary lesion was occult on mammography and biopsy yielded a lobular histology, breast MRI was performed. The MRI subtraction image shows a spiculated mass in the contralateral (left) breast (white arrow) and a small lesion located medially in the right breast (black arrow) (C). Biopsy yielded an invasive ductal carcinoma in the left breast and a fibroadenoma in the right breast.

18

Table 1. Characteristics of index cancers of bilateral screen-detected cancers and bilateral interval cancers

Index cancer± Screendetected N = 64

ED

PT

CC E A

P-value

38 (59.4) 26 (40.6)

16 (66.7) 8 (33.3)

IP T

0.53

0.18

A

35 (60.3) 23 (39.7)

0.09

15 (62.5) 9 (37.5) 0

U

N

39 (67.2) 12 (20.7) 7 (12.1)

0 24 (100)

SC R

6 (9.4) 58 (90.6)

M

Breast density of latest screening mammogram, n (%) 0-50% (ACR A&B) 50-100% (ACR C&D) Type of cancer, n (%) Ductal carcinoma in-situ Invasive cancer Histological type of invasive cancers, n (%) Ductal Lobular Other Tumour stage of invasive cancers, n (%) T1a-c T2-4 Lymph node status of invasive cancers, n (%) N+ No B&R grade of invasive cancers, n (%) I II III Unknown ER receptor status of invasive cancers, n (%) Positive Negative PR receptor status of invasive cancers, n (%) Positive Negative Her2/Neu receptor status of invasive cancers, n (%) Positive Negative Final surgical treatment, n (%) Breast conserving surgery

Index cancer Interval cancer N = 24

0.03

8 (33.3) 16 (66.7) 0.13

23 (39.7) 35 (60.3)

13 (54.2) 11 (45.8)

19 (32.8) 33 (56.9) 5 (8.6) 1 (1.7)

11 (45.8) 10 (41.7) 2 (8.3) 1 (4.2)

0.49

0.69 53 (91.4) 5 (8.6)

21 (87.5) 3 (12.5) 0.16

45 (77.6) 13 (22.4)

15 (62.5) 9 (37.5) 0.54

9 (15.5) 49 (84.5)

5 (20.8) 19 (79.2)

41 (64.1)

12 (50.0)

0.40

19

Mastectomy No surgery

±

21 (32.8) 2 (3.1)

11 (45.8) 1 (4.2)

In bilateral breast cancers, the cancer with the more advanced stage (or, in cases where both

tumours had the same stage, the larger tumour at pathology) was defined as the index tumour.

IP T

ACR = American College of Radiology; B&R = Bloom & Richardson; ER = estrogen; PR =

A

CC E

PT

ED

M

A

N

U

SC R

progesterone

20

Table 2. Characteristics of the index cancers and contralateral cancers of bilateral screen-detected cancers and bilateral interval cancers at biennial screening mammography Screen-detected cancers Index Contralateral cancer± cancer N=64 N=64

Histology of invasive cancers, n (%) Ductal Lobular Other Unknown

39 (67.2) 12 (20.7) 7 (12.l) 0

33 (73.3) 10 (22.2) 2 (4.4) 0

T-stage of invasive cancers, n (%) T1a-c T2-4 Unknown

35 (60.3) 23 (39.7) 0

40 (88.9) 5 (11.1) 0

Lymph node status of invasive cancers, n (%) N+ N-

23 (39.7) 35 (60.3)

0 24 (100) 0

3 (12.5) 21 (87.5) 0

15 (62.5) 9 (37.5) 0 0

18 (85.7) 0 2 (9.5) 1 (4.8)

U

SC R

0.001

0.001

A M

ED 19 (32.8) 33 (56.9) 5 (8.6) 1 (1.7)

<0.001

8 (33.3) 16 (66.7) 0

18 (85.7) 2 (9.5) 1 (4.8)

13 (54.2) 11 (45.8)

6 (28.6) 15 (71.4)

11 (45.8) 10 (41.7) 2 (8.3) 1 (4.2)

11 (52.4) 7 (33.3) 1 (4.8) 2 (9.5)

0.1

11 (24.4) 34 (75.6)

0.1

0.006 27 (60.0) 14 (31.1) 1 (2.2) 3 (6.7)

0.8

0.2 53 (91.4) 5 (8.6) 0

41 (91.1) 2 (4.4) 2 (4.4)

0.2 21 (87.5) 3 (12.5) 0

21 (100) 0 0

0.3 45 (77.6) 13 (22.4) 0

36 (80.0) 7 (15.6) 2 (4.4)

P-value

0.2

0.4

PT

CC E A

PR receptor status of invasive cancers, n (%) Positive Negative Unknown

Contralateral cancer N=24

IP T

16 (25.0) 45 (70.3) 3 (4.7)

ER receptor status of invasive cancers, n (%) Positive Negative Unknown

Index cancer N=24

0.006 6 (9.4) 58 (90.6) 0

B&R grade of invasive cancers, n (%) I II III Unknown

Pvalue

N

Type of cancer, n (%) Ductal carcinoma in situ Invasive cancer Unknown

Interval cancers

0.1 15 (62.5) 9 (37.5)

18 (85.7) 3 (14.3) 0 21

0 Her2/Neu receptor status of invasive cancers, n (%) Positive Negative Unknown

0.1

±

5 (11.1) 37 (82.2) 3 (6.7)

41 (64.1) 21 (32.8) 2 (3.1)

43 (67.2) 17 (26.6) 4 (6.3)

5 (20.8) 19 (79.2) 0

1 (4.8) 20 (95.2) 0

12 (50.0) 11 (45.8) 1 (4.2)

12 (50.0) 11 (45.8) 1 (4.2)

1

IP T

0.6

SC R

Final surgical treatment, n (%) Breast conserving surgery Mastectomy No surgery

9 (15.5) 49 (84.5) 0

0.2

In bilateral breast cancers, the cancer with the more advanced stage (or, in cases where both

tumours had the same stage, the larger

U

tumour at pathology) was defined as the index tumour.

ED

M

A

N

B&R = Bloom & Richardson; ER = estrogen; PR = progesterone

Table 3. Characteristics of contralateral cancers of bilateral screen-detected and

A

CC E

PT

bilateral interval cancer.

22

Contralateral cancer± Screendetected N = 64

PT

CC E A

P-value

0.3 16 (25.0) 45 (70.3) 3 (4.7)

3 (12.5) 21 (87.5) 0

33 (73.3) 10 (22.2) 2 (4.4) 1 (4.8)

18 (85.7) 0 2 (9.5) 1 (4.8)

IP T

0.048

0.5

18 (85.7) 2 (9.5) 1 (4.8)

SC R

40 (88.9) 5 (11.1) 0

N A

M

27 (60.0) 14 (31.1) 1 (2.2) 3 (6.7)

41 (91.1) 2 (4.4) 2 (4.4)

0.8

6 (28.6) 15 (71.4)

U

11 (24.4) 34 (75.6)

ED

Type of cancer, n (%) Ductal carcinoma in-situ Invasive cancer Unknown Histological type of invasive cancers, n (%) Ductal Lobular Other Unknown Tumour stage of invasive cancers, n (%) T1a-c T2-4 Unknown Lymph node status of invasive cancers, n (%) N+ No Nottingham grading of invasive cancers, n (%) I II III Unknown Estrogen receptor status of invasive cancers, n (%) Positive Negative Unknown Progesterone receptor status of invasive cancers, n (%) Positive Negative Unknown Her2/Neu receptor status of invasive cancers, n (%) Positive Negative Unknown Final surgical treatment, n (%) Breast conserving surgery Mastectomy

Contralateral cancer interval cancer N = 24

0.8

11 (52.4) 7 (33.3) 1 (4.8) 2 (9.5) 1 21 (100) 0 0 1

36 (80.0) 7 (15.6) 2 (4.4)

18 (85.7) 3 (14.3) 0 0.5

5 (11.1) 37 (82.2) 3 (6.7)

1 (4.8) 20 (95.2) 0 0.2

43 (67.2) 17 (26.6)

12 (50.0) 11 (45.8)

23

No surgery

±

4 (6.3)

1 (4.2)

In bilateral interval breast cancers, the cancer with the more advanced stage (or, in cases

where both tumours had the same stage, the larger

A

CC E

PT

ED

M

A

N

U

SC R

IP T

tumour at pathology) was defined as the index tumour

24